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NEW APPROACHES TO THE TREATMENT OF HEPATIC MALIGNANCIES |
From the Department of Surgical Oncology, The University of Illinois at Chicago, Chicago, Illinois.
Correspondence: Address correspondence and reprint requests to: Ira A. Jacobs, MD, Department of Surgical Oncology, The University of Illinois at Chicago, 840 S. Wood St. (M/C 820), Chicago, IL 60612; Fax: 312-996-9365; E-mail: iraallenjacobs{at}aol.com
ABSTRACT
Background: Thin melanomas have become increasingly prevalent, and lesions 
1 mm in thickness are frequently diagnosed. They are considered highly curable when treated solely with wide local excision, with reported 5-year disease-free survivals of 95% to 98%. However, thin Clark level III and IV melanomas may have increased potentials for metastasizing and late recurrences because of dermal lymphatics located at the interface of the papillary and reticular dermis. We have addressed this controversial area by reviewing the outcomes of patients with invasive thin melanomas.
Methods: We performed 266 sentinel lymph node biopsy procedures, using both radioisotope and blue dye, over a 5-year period. Sixty-five of the 266 invasive melanomas were thin and were treated by wide local excision and sentinel lymph node biopsy.
Results: Two (3%) of the 65 thin melanomas were found to have a positive sentinel lymph node. In melanomas thinner than .75 mm, no positive sentinel lymph node was found. Therefore, only 3% of patients may benefit from tumor upstaging by sentinel lymph node biopsy.
Conclusions: The occurrence of regional lymph node metastases in thin melanomas is rather low. Our data suggest that sentinel lymph node biopsy may not justified in patients with melanoma <.75 mm thick.
Key Words: Thin melanoma • Skin cancer • Sentinel node biopsy • Lymph node metastasis
The incidence of cutaneous melanoma is increasing worldwide, mainly because of an increased number of thin tumors. In the United States, melanoma incidence is increasing faster than any other cancer.1 Early diagnosis and increased public awareness is thought to be responsible for this change. Thin melanomas are considered highly curable when treated solely with wide local excision, with 5-year disease-free survival rates of 95% to 98%.2 Such high survival rates often preclude these patients from consideration for additional treatment.
It has been suggested that there may be a subset of patients at higher risk for recurrence from thin melanomas who may be treated more effectively with sentinel lymph node biopsy (SLNB) and/or adjuvant therapy with interferon alfa-2b than by wide local excision alone. Sentinel node studies3 have confirmed the absence of positivity in melanomas <.76 mm and 5% positivity in melanomas between 1.0 and 1.99 mm. The chance of regional lymph node involvement and, therefore, whether it is relevant to perform the sentinel node procedure, depends on the Breslow thickness of the primary tumor. However, a Breslow thickness cutoff point has not yet been established. We evaluated a patient population with melanoma that had undergone a sentinel node procedure to determine this point, so that the procedure can be restricted to a smaller group of patients in the future.
METHODS
Patient Population
Over a 5-year period, 259 patients with cutaneous malignant melanoma underwent 266 lymphatic mapping and sentinel node biopsy procedures by members of the Department of Surgical Oncology at the University of Illinois at Chicago Medical Center. No patients had clinically palpable lymph nodes. All patients satisfied the following inclusion criteria: the patient had a histologically proven malignant melanoma by incisional biopsy, punch biopsy, or excision; no skin grafting or flaps had been performed; and the diagnosis was established <2 months before the sentinel node procedure. Sixty-three patients had thin melanomas (<1.0 mm in thickness) and underwent SLNB at the time of their wide local excision. These patients form the basis for this review
The study population was approximately evenly distributed between the sexes. They had a mean age of 53 years (range, 20–84 years). Mean Breslow thickness was .67 mm (range, .1–.98 mm). All lesions were retrospectively reviewed to ensure that a deeper lesion was not identified. Locations of the primary lesion were the trunk in 39%, lower extremity in 26%, head and neck in 18%, and upper extremity in 17%. Detailed patient characteristics are listed in Table 1. With a mean follow-up of 27 months (range, 6–60 months), all patients remained alive with no evidence of disease at last follow-up.
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Intraoperative Lymphatic Mapping
The location of lymphatic channels and sentinel nodes was confirmed by using a handheld gamma probe (Navigator GPS; USSC, Norwalk, CT) and was marked on the skin with indelible ink. When two or more drainage patterns were identified for the primary melanoma, each was considered separately with respect to lymphatic mapping. Counts were measured over the primary melanoma and along the lymphatic channels draining to the lymphatic basin. These counts were compared with a background measurement made at a neutral site away from the primary melanoma and the lymphatic basins, so as to avoid confusion with radioactivity emitted from the "hot" regions. Measurements were recorded over the hottest node in the lymphatic basin before skin incision. The skin incision was incised in a way that the incision could be incorporated into a subsequent lymphadenectomy scar. The first sentinel node was identified, and counts were measured before (in vivo) and after (ex vivo) its excision. The gamma probe was used to measure residual counts in the lymphatic basin and to identify any additional sentinel nodes. After all sentinel nodes were removed, the residual radioactivity in the lymphatic basin was measured (after excision). The primary melanoma was then excised (if this had not previously been done) with margins of 1 cm. In cases in which the primary melanoma and sentinel lymph node (SLN) were in close proximity to one another, the primary excision was performed first to facilitate detection of the SLN.
Histopathologic Examination of Sentinel Lymph Node Specimens
Each sentinel node was bisected from hilum to periphery and then fixed in 10% neutral buffered formalin, embedded in paraffin, and sectioned. The nodal sections were then processed for routine hematoxylin and eosin (H&E) staining and for immunoperoxidase staining by using antibodies to HMB-45 and melan-A protein. Both negative and positive control stains were run simultaneously with the specimens to confirm the sensitivity and specificity of the immunohistochemical method. SLNs were level-sectioned for routine H&E three times and for HMB-45 and melan-A immunohistochemistry two times. Non-SLNs were studied in the same manner.
RESULTS
Distribution of Mapped Basins
Sixty-three patients underwent 65 lymphatic mapping and sentinel lymphadenectomy procedures. Seventy-one lymph node basins were mapped in the 65 procedures. Axillary, inguinal, and cervical nodal basins comprised 48%, 32%, and 20% of the total basins evaluated, respectively. Fifty-nine patients (91%) underwent lymphatic mapping of one regional nodal basin, and six patients (9%) underwent synchronous lymphatic mapping of two regional nodal basins. At least one SLN was identified in all of the 71 basins mapped.
Histological Status of SLN
A positive SLN was identified by histological analysis in two (3%) patients. Both of these patients then had the blocks of their primary tumor further sectioned to determine that there was not a deeper lesion undiagnosed on the original examination. Of these, one patient underwent a therapeutic lymphadenectomy, and the other refused operation. The former was a 43-year-old man with a .75-mm-thick, Clark level III superficial spreading melanoma on his back. The SLN was identified in his axilla, and no metastasis was noted in the H&E-stained sections. However, a single cell was positive with the immunostains for HMB-45 and melan-A. The patient underwent a completion axillary lymphadenectomy, and no additional metastatic melanoma was identified in the remaining 26 lymph nodes. He refused to receive adjuvant therapy, and no other adjuvant therapy was offered. He remains free of disease 21 months after lymphadenectomy.
The second patient was a 23-year-old man with a .9-mm-thick, Clark level IV, superficial spreading melanoma of his ear. The SLN was identified in his parotid gland. No metastasis was noted in the H&E-stained sections. Immunostain for S-100 showed a focus of strong positive-staining cells, whereas melan-A showed a weaker positive staining in the same cells. This was considered consistent with metastatic malignant melanoma. Immunostain for HMB-45 was negative. He refused additional surgical intervention and all forms of adjuvant therapy, including interferon and radiotherapy to the nodal basin. He remains free of disease 22 months after his sentinel lymphadenectomy.
DISCUSSION
Malignant melanoma has increased in incidence during the last decade at a rate faster than any other malignancy in the United States. Despite a 10% rate of annual increase in incidence, there has been a deceased mortality rate from melanoma over the years.4 This is most likely secondary to earlier detection and treatment of these lesions.
For many years, the subject of elective lymph node dissection had been one of the most important controversies in the management of patients with malignant melanoma. Determining the status of the regional lymph nodes is critical in staging patients with newly diagnosed melanoma, because lymph node involvement is known to be the most important prognostic factor. Most patients with primary cutaneous malignant melanoma present without clinically enlarged lymph nodes. However, approximately 15% of these patients harbor occult lymph node micrometastases.5 Accurate diagnostic identification of such lymph node metastases in melanoma patients is important for selecting patients to receive adjuvant therapy and for enrollment in experimental protocols. In an attempt to solve this problem, location of the first-echelon lymph node by means of the sentinel node procedure has gained increasing acceptance over the past decade and is now the standard of care in the treatment and evaluation of patients with malignant melanoma.
The methods of SLN biopsy have been described thoroughly in the literature with the combination of vital blue dye mapping and intraoperative radiolymphoscintigraphy.6 With the combination of these two methods, localization is easier and more widely applicable. SLN histology reflects the status of the nodal basin with accurate pathologic staging without compromising the standards of care. Morbidity is reduced with no lymphedema, and earlier return to work and normal activity is seen. Costs are also decreased by the use of local anesthesia for these techniques.
A 1-cm margin of excision for melanomas <1 mm in thickness has been shown to be adequate for local control and does not influence the timing or development of regional nodal or distant metastases.7 Historically, it was believed that thin (.76-mm) melanomas never recurred after simple excision.8 Other investigators have reported on recurrences and deaths from stage I melanomas <.76 mm in thickness.9,10 The ability of thin melanomas to metastasize had been previously studied. Kelly et al.11 reported that patients with Clark level IV .6- to 1.1-mm-thick melanomas have a poor prognosis. Slingluff et al.12 reported that metastases developed in 18.6% of the patients with thin melanomas. Patients at high risk were found to have an actuarial risk of 11% for metastases at 5 years and 22% at 10 years.
Recent compelling data demonstrate that the involvement of regional nodes in thin melanomas is very uncommon. An overwhelming number of sentinel node studies have confirmed the absence of positivity in melanomas <.76 mm and 5% positivity in melanomas between 1.0 and 1.99 mm.3 The incidence of regional lymph node involvement correlates, as is expected, with the Breslow thickness of the primary tumor. However, a Breslow thickness cutoff point has not yet been definitively established. The occurrence rate of nodal metastasis in our group of patients was 3%; this is consistent with the 3% to 7% frequency of recurrent disease for thin melanomas reported in the literature.13 No positive sentinel nodes were found in melanomas thinner than .75 mm. Our data suggest that sentinel lymphadenectomy is not indicated for melanomas <.75 mm in thickness. Patients with melanomas >.75 mm but <1.0 mm in thickness have a 3% incidence of nodal metastasis and may benefit from SLNB.
Because of the increasing incidence of malignant melanoma, coupled with better public awareness, more patients with thinner primary lesions are presenting to clinicians. There is neither a biological basis nor clinical evidence to support SLNB in these patients. The cutoff point for nodal involvement seems to be .75-mm thickness. The challenge is to be able to identify, at the time of initial diagnosis, those patients with thin primary melanoma that will behave aggressively so a more aggressive approach may be taken toward their care.
Acknowledgments
The authors thank the following people, whose contributions were indispensable: Susan Simon, CTR, for data acquisition, and Vida Vizgirda, RN, PhD, for biostatistical analysis and review of the manuscript.
The acknowledgments are available online at www.annalssurgicaloncology.org.
Footnotes
The occurrence of regional lymph node metastases in thin melanomas is rather low. Our data suggest that sentinel lymph node biopsy may not justified in patients with melanoma <.75 mm thick.
Received for publication October 28, 2002. Accepted for publication February 12, 2003.
REFERENCES
This article has been cited by other articles:
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K. B. Stitzenberg, P. A. Groben, S. L. Stern, N. E. Thomas, T. A. Hensing, L. B. Sansbury, and D. W. Ollila Indications for Lymphatic Mapping and Sentinel Lymphadenectomy in Patients with Thin Melanoma (Breslow Thickness <=1.0 mm) Ann. Surg. Oncol., October 1, 2004; 11(10): 900 - 906. [Abstract] [Full Text] [PDF]
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